Stroke Flashcards
Stroke facts
2nd leading cause of death worldwide
20-33% die within 1-3 months
Largest cause of adult disability in uk
25% of cases on people under 65
What is a stroke
Brain attack caused by the disturbance of blood supply to the brain
Rapidly developing clinical symptoms, focal or global, leading to loss of cerebral function that can only be attributed to vascular origin
Acute effect of stroke vs chronic brain disease
Rapid presence of symptoms vs build up over time
Obstacle to emergency treatment of stroke
Don’t know they are having a stroke
Long time between stroke and getting to the hospital
F - face
A - arms
S - speech
T - time
Ischemic stroke
Blood clot so blood flow stops so cells don’t get oxygen
Haemorrhagic stroke
Rupture of blood vessels
Intracerebral haemorrhage - blood spilled over brain, 10% of strokes
Subarachnoid haemorrhage - 5% of stroke
Transient ischemia attack (TIA)
Ischdmic events
Resolves with 24 hrs
No tissue death
Intracerebral haemorrhage
Blood goes into the premnchyal, invades brain tissue, invades neurones and glial cells, haemoglobin comes out (some neurones sub lethal exposure but have effect)
Extracellular haemoglobin induces cell death mainly via oxidation and inflammation
Subarachnoid haemorrhage
Venous sinus leak
Invades subarahnoid space and spreads around brain at high pressure
Blood released into subarachnoid space clots almost immediately and disappears via clot lysis which starts shortly after SAH
Highest incidence of death and disability and in younger people
Cerebral venous sinus thrombosis (CVST) EXTRA READING
Ischemic stroke
Aka thrombotic
85% of strokes
Usually in medial cerebral artery - arm and facial weakness, speech affected but depends on location Lenticulostriate arteries in lacunar stroke (most common, the small areas following MCA) - weakness on one side of the body
The brain needs to be adequately perfumed
Uses up most energy
Expensive to run in term of energy (ATP)
20% of energy
15% of cardiac output
(Sodium/potassium pump)
Brainstem stroke syndromes
Can affect fibre tracts (eg spinothalamic tract, nuclei (of cranial nerves) and physiological functions (eg consciousness and arousal)
Occlusion of vessel in posterior circulation
Stroke syndromes: medulla - wallenbergs syndrome, midbrain - webers syndrome, pons - locked in syndrome
Clinical features of brainstem strokes: tracts
Motor/sensory disturbance
Ataxia
Horners syndrome
Clinical features of brainstem strokes: nuclei
Cranial nerve dysfunction
Clinical features of brainstem strokes: physiological centres
Loss of consciousness
Stroke progression
Rapid - o2 depletion, energy failure, terminal depol, ion homeostasis failure (minutes)
Secondary - excitotoxicity, SD like depols, disturbance of ion homeostasis (hours to days)
Delayed - inflammation, apoptosis (days to weeks)
Current treatments for stroke
Antiplatelets
Clot busting agent aka alteplase
Anticoagulants
Carotid endarterectomy
Statins
Anti hypertensives
Neurosurgery- remove blood and repair burst blood vessels
Clot busting agent aka alteplase
Mainly used
Has to be given within 4 hrs so only 8% of patients eligible
Correct diagnosis extremely important
Eg Haemorrhagic cannot be given clot busting or will bleed to death
Must act fast for treatments
How is the clinical outcome of stroke measured
National institutes of health stroke scale (NIHSS)
Bigger the score the worse off they are
Improved outcome with earlier treatment
Risk factors of stroke
High blood pressure
Elevated cholesterol level
Smoking
Physical inactivity
Obesity
Alcohol consumption
60-80 % cumulative stroke risk
Non modifiable risk factors - older age, race (Hispanic, black), maternal history of stroke, sex (makes), diabetes
How do risk factors increase the propensity to stroke
Structure and function of blood vessels - artherosclerosis, stiffening of arteries, narrowing thickening and tortuosity of aerterioles and capillaries eg atheroma, aneurysm
Interface with circulating blood - reduction/ alteration of cerebral flow (CBF)
Inflammatory cells - macrophages, T lymphocytes, mast cells, cascade - lesion development
Stroke triggers can be identified in some patients
Neck trauma
Pregnancy/ postpartum
Systemic infection use of drugs
Mental stress
Exacerbation of vascular inflammation, activation of coagulation cascade leading to vascular occlusion and haemodynamic insufficiency
Ten point plan for action
Awareness
Prevention
Patient involment
Act on warnings
Stroke as medical emergency
Stroke uni quality
Rehabilitation and community support
Participantion
Workforce
Service improvement
<50% of hospitals with acute stroke units have brain scanning available within 3 hrs
Stroke (cells involved)
Interactions between glia, neurons, vascular cells, matrix components all relevant
Normal aerobic metabolism
Oxygen + glucose lead to mitochondrial respiration to create cellular ATP produces and so ongoing consumption
Stroke influence on aerobic respiration
Removal of mitochondrial respiration
So depletion of ATP
Accumulation of reactive oxygen species so even more ATP usage so intracellular acidification
Malfunction and cellular death
Malfunction of ATP dependent processes
Enhanced consumption of cellular ATP
Profound loss of ioninc gradients so sustained rise in [glu]o (further loss of ionic gradients) and large elevations of intracellular calcium leading to excitotoxicity due to more ROS, proteases and mitochondrial Ca overload
Inflammation
Ischemia evokes robust inflammatory response
Highly stereotyped and markers used to determine approximate age of cerebrovascular lesions
Stimulated glia and blood vessels communicate through complex signalling
Innate and adaptive immune systems used
Early vascular, peri vascular and parenchyma events triggered by ischemia and reperfusion
Clot - stress/ pressure
Clot goes away - perfusion stress/pressure
Signals interact with BBB and may open it so may infiltrate the brain
Increase in ROE and decrease in nitric oxide produced by blood vessels
Interact with neurones and astrocytes
Cell death and activation pattern, recognition receptors set the stage adaptive immunity
Neurones may release ATP or UTP in cells that have been opened by force and may leak out signal danger molecules
Eg HMGB1, HSP60, AB
Activate TLR 2 and 4
Lead to adaptive immunity, leukocyte infiltration, tissue damage and matrix degredation leading to DAMPs activation
Inflammation appliqués Ischemic lesion early on
Resolution of inflammation and tissue repair
Microglia start to clear away dead cells
Start release neuro protective factors eg IL10 and TGF-B
Brain repair - neurones release helpful factors eg BDNF, VEGF to repair neurones and blood vessels
Peripheral immunological changes after stroke
Blood, bone marrow, spleen and other lymphoid organs
White blood cell count and expression of cytokines and inflammatory markers up within hrs after ischemia then down within 1/2 days
Marked immuno depression - determinant of stroke morbidity and morality
Respiratory and UTIs
Ischemia penumbra
Area of reduced perfusion sufficient to cause potentially reversible clinical deficits but insufficient to cause disrupted ionic homeostasis
Contribution factors for irreversible damage of brain tissue in penumbra
Ischemic core
Irreversibly damaged tissue <20% baseline blood flow levels
Depleted ATP stores
Failure energy metabolism
Ischemic penumbra
Perinfract zone
Depressed tissue perfusion
Basal ATP lvls & o2 metabolism
Normal ion gradients
Electrical silence
Suppressed protein synthesis
Goes from salvageable tissue to dead within hrs and days
MRI (DWI & PWI) - Acute ischemic stroke
Diffusion weighted imaging
Detects areas of restricted diffusion of water - bright in acute Ischemic stroke
Perfusion weighted imaging
Detects abnormal blood flow
Diffusion perfusion mismatch
Salvageable brain to infractionsteps
Energy failure
Anoxic depol, excitotoxicity, oxidative stress, necrosis
Peri infract depol, calcium overload, mitochondrial damage
Inflammation, programmed cell death
Interacted tissue
Studying stroke
Patients (post mortem, clinical trials)
Animal models (eg medial cerebral artery occlusion)
In vitro studies ( eg oxygen glucose deprivation)
Possible stroke treatment - time sundowns and convo therapy approaches (EXTRA READING)
Reversal of focal ischemia
Animal model (rat)
Mechanical occlusion of middle cerebral artery for 1 hr
Imaging of ATP and protein synthesis
Restoration of energy metabolism but not protein synthesis
Restoration of energy metabolism fails where protein synthesis did not recover
Simulated ischemia in neurones causes sharp increase in glutamate receptor activation and anoxic depol (AD)
Glutamate mediate feedback mechanism that doesn’t let recover
Under Ischemic conditions, disruptions na+, k+ and pH gradients will cause transported to function in reverse leading to increased [extracellular glutamate]
Potential therapy: glutamate/ca receptor blockers
Protect neurons from 1.5 hrs oxygen/glucose depreciation
Don’t protect >2 hrs
Possible involvement of NMDARs, TRPM2 & 7 channels in anoxic neuronal death
Excessive activation of glutamate receptors
Activation of NMDA receptor subtype (voltage dependent)
Losing membrane potential, receptors bound to glutamate and open as cell is depolarised
Calcium influx
Activation of ion channels TRMP2 & 7
Interact with mitochondria so ROS
Essential interaction of nitric oxide synthase with PSD95 bound to NMDA receptors
Peroxinitrate (ROS) lead to cell death
Nitric oxide
Multifunction biological messenger
Reduction in nitric oxide in vascular system - bad
High levels bad in neurones
Endothelial nitric oxide
Vasoregikatory effects
Antiaggregant
Antiprolifarative
Anti cell adhesion
Nitric oxide loss leads to vasoconstriction- platelet aggregation, leukocyte adhesion to endothelial cells, smooth muscle proliferation, key steps to vascular inflammation
Inhibiting NOS reduces number of dead cells by NMDA application in cultured cells
[L-NAME] increase can rescue some cells as it is a NOD inhibitor
Knock down PSD-95 reduced number of dead neurons following NMDA application
Treatment with agent that perturbs PSD95 interactions - inefficient signalling through PSD 95 bound effector molecules by keeping NOS away
Treatment of stroke with PSD95 inhibitor in primate brain
Decreased infraction compared to placebo condition
Primate - closer to humans
N1-A treatment
40% decrease in morbidity
Functional independence - 10% increase
Good to give to all stroke types - give in ambulance, more likely to survive
